Elucidation of epigenetic gene regulation mechanism for establishment of new therapeutic strategies for severe infectious diseases

• Project/Area Number: 15K09580
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Keio University
• Principal Investigator: ISHII Makoto 慶應義塾大学, 医学部(信濃町), 講師 (30317333)
• Co-Investigator(Renkei-kenkyūsha): NAKAYAMA Toshinori 千葉大学, 医学部免疫発生学教室, 教授 (50237468)
• Research Collaborator: YAGI Kazuma
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 重症感染症 / エピジェネティクス / インフルエンザ / 肺炎球菌 / ヒストンアセチル化 / 肺炎球菌性肺炎 / ヒストンメチル化 / Ezh2 / HDAC阻害薬 / 肺炎球菌感染

Outline of Final Research Achievements

The hypothesis of the study was epigenetic mechanism, especially for histone acetylation, might contribute to the poor outcome of post-influenza pneumonia. Mice were infected intranasally with 1.0 × 104 CFU of Streptococcus pneumoniae 7 days after intranasal inoculation with 5 PFU of influenza virus A/PR8.The mice were intraperitoneally injected with the histone deacetylase (HDAC) inhibitor TSA. TSA significantly suppressed HDAC activity and significantly improved the survival rate of mice after post-influenza pneumococcal infection, which was associated with a significant decrease in bacterial load and the total cell count of the BALF. The number of natural killer cells in the lungs were significantly lower in the TSA-treated group, which may contribute to the protective effects of TSA.
TSA protects mice against post-influenza pneumococcal pneumonia possibly through multiple factors, including a decrease in lung and systemic bacterial load, and suppression of systemic inflammation.

Research Products

• [Journal Article] Clinical characteristics of pulmonary Mycobacterium lentiflavum disease in adult patients. (2018)
  • Author(s): Yagi K, Morimoto K, Ishii M, Namkoong H, Okamori S, Asakura T, Suzuki S, Asami T, Uwamino Y, Funatsu Y, Fujiwara H, Kamata H, Nishimura T, Betsuyaku T, Kurashima A, Hasegawa N.
  • Journal Title: International Journal of Infectious Diseases Volume: 67 Pages: 65-69
  • DOI: 10.1016/j.ijid.2017.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Natural history of Mycobacterium fortuitum pulmonary infection presenting with migratory infiltrates: a case report with microbiological analysis. (2018)
  • Author(s): Okamori S, Asakura T, Nishimura T, Tamizu E, Ishii M, Yoshida M, Fukano H, Hayashi Y, Fujita M, Hoshino Y, Betsuyaku T, Hasegawa N
  • Journal Title: BMC Infectious Diseases Volume: 18(1) Issue: 1 Pages: 1-1
  • DOI: 10.1186/s12879-017-2892-9
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Cavity and Infiltration on Pulmonary Function and Health-Related Quality of Life in Mycobacterium avium complex Pulmonary Disease: A 3-Dimensional Computed Tomographic Analysis (2017)
  • Author(s): Asakura T, Yamada Y, Namkoong H, Suzuki S, Niijima Y, Kamata H, Funatsu Y, Yagi K, Okamori S, Sugiura H, Ishii M, Jinzaki M, Betsuyaku T, Hasegawa N
  • Journal Title: Respir Med Volume: 126 Pages: 9-16
  • DOI: 10.1016/j.rmed.2017.03.010
  • Peer Reviewed / Open Access
• [Journal Article] Glycoprotein Nanotube Traps Influenza Virus. (2017)
  • Author(s): Yuge S, Akiyama M, Ishii M, Namkoong H, Yagi K, Nakai Y, Adachi R, Komatsu T.
  • Journal Title: Chem Lett Volume: 41(1) Pages: 95-97
  • NAID: 130005308379
• [Journal Article] Long-term Outcome of Pulmonary Resection for Nontuberculous Mycobacterial Pulmonary Disease (2017)
  • Author(s): Asakura T, Hayakawa N, Hasegawa N, Namkoong H, Takeuchi K, Suzuki S, Ishii M, Bestuyaku T, Abe Y, Ouchi M
  • Journal Title: Clin Infect Dis Volume: in press Issue: 2 Pages: 244-251
  • DOI: 10.1093/cid/cix274
  • Peer Reviewed
• [Journal Article] Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung (2017)
  • Author(s): Kuroda Aoi、Hegab Ahmed E.、Jingtao Gao、Yamashita Shuji、Hizawa Nobuyuki、Sakamoto Tohru、Yamada Hideyasu、Suzuki Satoshi、Ishii Makoto、Namkoong Ho、Asakura Takanori、Ozaki Mari、Yasuda Hiroyuki、Hamamoto Junko、Kagawa Shizuko、Soejima Kenzo、Betsuyaku Tomoko
  • Journal Title: Respir Res Volume: 18 Issue: 1 Pages: 69-69
  • DOI: 10.1186/s12931-017-0554-5
  • NAID: 120007129115
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases. (2017)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Iketani O, Asakura T, Suzuki S, Sugiura H, Yamada Y, Nishimura T, Fujiwara H, Funatsu Y, Uwamino Y, Kamo T, Tasaka S, Betsuyaku T, Hasegawa N
  • Journal Title: BMC Infectious Diseases Volume: 17(1) Issue: 1 Pages: 558-558
  • DOI: 10.1186/s12879-017-2665-5
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and radiological characteristics of patients with late-onset severe restrictive lung defect after hematopoietic stem cell transplantation (2017)
  • Author(s): Namkoong Ho、Ishii Makoto、Mori Takehiko、Sugiura Hiroaki、Tasaka Sadatomo、Sakurai Masatoshi、Koda Yuya、Kato Jun、Hasegawa Naoki、Okamoto Shinichiro、Betsuyaku Tomoko
  • Journal Title: BMC Pulmonary Medicine Volume: 17 Issue: 1 Pages: 123-123
  • DOI: 10.1186/s12890-017-0466-7
• [Journal Article] Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease. (2017)
  • Author(s): Kamata H1, Asakura T1,2, Suzuki S1,2, Namkoong H1, Yagi K1, Funatsu Y1, Okamori S1, Uno S3, Uwamino Y4, Fujiwara H3, Nishimura T5, Ishii M1, Betsuyaku T1, Hasegawa N6.
  • Journal Title: BMC Pulmonary Medicine Volume: 17(1) Issue: 1 Pages: 198-198
  • DOI: 10.1186/s12890-017-0544-x
  • Peer Reviewed / Open Access
• [Journal Article] Sternoclavicular joint osteomyelitis extending to lung abscess complicated by Staphylococcal infective endocarditis. (2017)
  • Author(s): Masuzawa K, Asakura T, Ishii M, Yasuda H, Sugiura H, Betsuyaku T.
  • Journal Title: IDCases Volume: 9 Pages: 36-37
  • DOI: 10.1016/j.idcr.2017.04.005
  • Peer Reviewed / Open Access
• [Journal Article] Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports (2017)
  • Author(s): Okamori S, Asakura T, Masuzawa K, Yasuda H, Kamata H, Ishii M, Betsuyaku T.
  • Journal Title: Medicine(Baltimore) Volume: 96 Issue: 49 Pages: e9081-e9081
  • DOI: 10.1097/md.0000000000009081
  • Peer Reviewed / Open Access
• [Journal Article] Bilateral upper lobe Pneumocystis pneumonia during aerosolized pentamidine prophylaxis. (2017)
  • Author(s): Ohara Y, Asakura T, Ueda S, Yamada Y, Ishii M, Betsuyaku T.
  • Journal Title: QJM Volume: in press Issue: 5 Pages: 337-338
  • DOI: 10.1093/qjmed/hcx233
  • Peer Reviewed / Open Access
• [Journal Article] Histone Deacetylase Inhibition Protects Mice against Lethal Post-Influenza Pneumococcal Infection. (2016)
  • Author(s): Yagi K, Ishii M, Namkoong H, Fujii H, Asami T, Suzuki S, Asakura T, Mizoguchi K, Kamo T, Tasaka S, Iwata S, Kunkel SL, Hasegawa N, Betsuyaku T.
  • Journal Title: Crit Care Med. Volume: 44(10) Issue: 10 Pages: e980-e987
  • DOI: 10.1097/ccm.0000000000001821
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical characteristics of pulmonary Mycobacterium scrofulaceum disease in 2001-2011: a case series and literature review (2016)
  • Author(s): Suzuki S, Morino E, Ishii M, Namkoong H, Yagi K, Asakura T, Asami T, Fujiwara H, Uwamino Y, Nishimura T, Tasaka S, Betsuyaku T, Takasaki J, Iwata S, Hasegawa N
  • Journal Title: J Infect Chemother Volume: 22 Issue: 9 Pages: 611-616
  • DOI: 10.1016/j.jiac.2016.06.006
  • Peer Reviewed
• [Journal Article] Pneumothorax Associated with Nontuberculous Mycobacteria: A Retrospective Study of 69 Patients (2016)
  • Author(s): Ueyama M, Asakura T, Morimoto K, Namkoong H, Matsuda S, Osawa T, Ishii M, Hasegawa N, Kurashima A, Goto H
  • Journal Title: Medicine (Baltimore) Volume: 95 Issue: 29 Pages: e4246-e4246
  • DOI: 10.1097/md.0000000000004246
  • Peer Reviewed / Open Access
• [Journal Article] Macrolide-resistant Mycobacterium avium complex –An analysis of 102 consecutive cases. (2016)
  • Author(s): Morimoto K, Namkoong H, Hasegawa N, Nakagawa T, Morino E, Shiraishi Y, Ogawa K, Izumi K, Takasaki J, Yoshiyama T, Hoshino Y, Matsuda S, Hayashi Y, Sasaki Y, Ishii M, Kurashima A, Nishimura T, Betsuyaku T, Goto H; Nontuberculous Mycobacteriosis Japan Research Consortium (NTM-JRC)
  • Journal Title: Ann Am Thorac Soc. Volume: 13(11): Issue: 11 Pages: 1904-1911
  • DOI: 10.1513/annalsats.201604-246oc
  • Peer Reviewed
• [Journal Article] Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression. (2016)
  • Author(s): Takahashi S, Ishii M, Namkoong H, Hegab AE, Asami T, Yagi K, Sasaki M, Haraguchi M, Sato M, Kameyama N, Asakura T, Suzuki S, Tasaka S, Iwata S, Hasegawa N, Betsuyaku T.
  • Journal Title: J Infect Dis Volume: 213(6) Issue: 6 Pages: 1018-1030
  • DOI: 10.1093/infdis/jiv527
  • Peer Reviewed
• [Presentation] The Critical Role of a Disintegrin and Metalloprotease (ADAM) 10 During Severe Influenza Virus Infection In Vivo and In Vitro. (2017)
  • Author(s): Okamori S, Ishii M, Asakura T, Suzuki S, Kamata H, Namkoong H, Yagi K, Kagawa S, Kamo T, Asami T, Horiuchi K, Hasegawa N, Betsuyaku T.
  • Organizer: The 113th annual International Conference of American thoracic society.
  • Int'l Joint Research
• [Presentation] S1P Receptor Modulation Expands CD11b+Gr-1+ Cells and Inhibits Lymphocyte Infiltration in the Lungs and Ameliorate Murine Pulmonary Emphysema. (2017)
  • Author(s): Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Komiya T, Yagi K, Kamata H, Okamori S, Asami T, Hasegawa N, Betsuyaku T.
  • Organizer: The 113th annual International Conference of American thoracic society.
  • Int'l Joint Research
• [Presentation] A Case of Cutis Laxa with Juvenile Emphysema Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN). (2017)
  • Author(s): Namkoong H, Ishii M, Yagi K, Chubachi S, Tsuji S, Kosaki K, Betsuyaku T.
  • Organizer: The 113th annual International Conference of American thoracic society.
  • Int'l Joint Research
• [Presentation] Protective Role of a Disintegrin and Metalloprotease 17 (ADAM17) in Elastase-Induced Emphysema in Mice. (2017)
  • Author(s): Suzuki S, Ishii M, Asakura T, Namkoong H, Okamori S, Yagi K, Kamata H, Kagawa S, Horiuchi K, Hasegawa N, BetsuyakuT.
  • Organizer: The 113th annual International Conference of American thoracic society.
• [Presentation] The Histone Deacetylase Inhibitor Trichostatin A Protects Mice Against Lethal Post-Influenza Pneumococcal Infection. (2016)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Asakura T, Suzuki S, Fujiwara H, Nishimura T, Kamo T, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 112th annual International Conference of American thoracic society. .
  • Place of Presentation: San Francisco, CA, U.S.A
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] 3-Deazaneplanocin A-an Inhibitor of Histone Methyltransferase Ezh2-Exacerbates Elastase-Induced Emphysema in Mice. (2016)
  • Author(s): Asakura T, Ishii M, Namkoong H, Yagi K, Suzuki S, Tanosaki T, Kagawa S, Kamo T, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 112th annual International Conference of American thoracic society.
  • Place of Presentation: San Francisco, CA, U.S.A
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Obesity Worsens the Outcome of Influenza Virus Infection Via Impaired IFN -Beta Induction and Reduced Expressions of Antimicrobial Peptides in Mice. (2016)
  • Author(s): Namkoong H, Ishii M, Fujii H, Yagi K, Asakura T, Suzuki S, Kamata H, Hasegawa N, Betsuyaku T.
  • Organizer: The 112th annual International Conference of American thoracic society.
  • Place of Presentation: San Francisco, CA, U.S.A
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Critical Role of the Prostaglandin D2 Receptor CRTH2 in Acute Lung Injury Caused by Lipopolysaccharide (LPS)-Induced Shock in Mice. (2016)
  • Author(s): Suzuki S, Ishii M, Asami T, Namkoong H, Yagi K, Asakura T, Kamata H, Tasaka S, Kagawa S, Kamo T, Asano K, Nakamura M, Hirai H, Nagata K, Hasegawa N, Betsuyaku T.
  • Organizer: The 112th annual International Conference of American thoracic society
  • Place of Presentation: San Francisco, CA, U.S.A
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Role of histone acetylation in mice coinfected with influenza virus and Streptococcus pneumonia. (2015)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Asakura T, Suzuki S, Fujiwara F, Nishimura T, Kamo T, Tasaka T, Hasegawa N, Betsuyaku T.
  • Organizer: The 111th annual International Conference of American thoracic society
  • Place of Presentation: デンバー（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] The critical roles of tumor necrosis factor -converting enzyme during influenza virus and Streptococcus pneumoniae infection in vivo and in vitro. (2015)
  • Author(s): Suzuki S, Ishii M, Namkoong H, Yagi K, Asakura T, Tasaka S, Kamo T, Kagawa S, Fujiwara H, Nishimura T, Horiuchi K, Hasegawa N, Betsuyaku T.
  • Organizer: The 111th annual International Conference of American thoracic society.
  • Place of Presentation: デンバー（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] Clarithromycin Expands CD11b+Gr-1+Cells to Ameliorate Post-Influenza Pneumococcal Pneumonia. (2015)
  • Author(s): Namkoong H, Ishii M, Fujii H, Yagi K, Asakura T, Suzuki S, Kamo T, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T.
  • Organizer: The 111th annual International Conference of American thoracic society.
  • Place of Presentation: デンバー（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] Levels of Soluble Receptor for Advanced Glycation End Products (sRAGE) in Bronchoalveolar Lavage Fluid in Patients with Various Lung Diseases. (2015)
  • Author(s): Kamo T, Tasaka S, Tokuda Y, Asakura T, Suzuki S, Yagi K, Namkoong H, Fujiwara H, Nishimura T, Ishii M, Hasegawa N, Betsuyaku T.
  • Organizer: The 111th annual International Conference of American thoracic society.
  • Place of Presentation: デンバー（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] 46.Asakura T, Ishii M, Funatsu Y, Yagi K, Namkoong H, Suzuki S, Kamo T, Asami T, Fujiwara F, 、Nishimura T, Tasaka S, Hasegawa N, Betsuyaku. Health-Related Quality of Life in 235 patients with Mycobacterium avium Complex Lung Disease in Japan. (2015)
  • Author(s): Asakura T, Ishii M, Funatsu Y, Yagi K, Namkoong H, Suzuki S, Kamo T, Asami T, Fujiwara F, 、Nishimura T, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 111th annual International Conference of American thoracic society.
  • Place of Presentation: デンバー（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] インフルエンザウイルス感染後肺炎球菌2次感染におけるヒストンセチル化の関与の検討 (2015)
  • Author(s): 八木一馬，石井誠，南宮湖，浅見貴弘，朝倉崇徳，鈴木翔二，藤原宏，西村知泰，加茂徹郎，田坂定智，長谷川直樹，別役智子．
  • Organizer: 第55回日本呼吸器学会総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2015-04-17
• [Presentation] Clarithromycin expands CD11b+Gr-1+cells to amerliorlate post-influenza pneumococcal pneumonia. (2015)
  • Author(s): Namkoong H, Ishii M, Fujii H, Yagi K, Asakura T, Shoji S, Kamo T, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T.
  • Organizer: 第55回日本呼吸器学会総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2015-04-17